Gout Flares and Mortality After Sodium-Glucose Cotransporter-2 Inhibitor Treatment for Gout and Type 2 Diabetes

Key Points Question What is the association between using sodium-glucose contransporter-2 inhibitors (SGLT2i) and the risk of recurrent gout flares among adults with gout and type 2 diabetes? Findings In this cohort study of 5931 patients with gout and type 2 diabetes, initiation of SGLT2i treatment was associated with 19% fewer recurrent gout flares and 29% lower mortality than initiation of active comparator treatments. Meaning These findings suggest that SGLT2i may reduce the burden of recurrent gout flares and narrow the mortality gap between patients with gout and the general population.


Introduction
Gout is the most common inflammatory arthritis. The prevalence and incidence of gout have risen worldwide for decades. 1 Although several efficacious pharmacologic regimens are available, many patients with gout continue to experience recurrent gout flares, 2 which cause excruciating pain and morbidity 3,4 and significantly affect activities of daily living. 5 Gout also carries substantial comorbidity burden from cardiovascular-metabolic conditions. 6,7 Furthermore, a number of studies have reported that gout increases the risk of death from kidney and cardiovascular disease, 8 and the secular trend of the mortality gap between patients with gout and the general population remains unimproved. 9 Current rheumatology guidelines recommend that patients with gout receive long-term therapy for lowering of urate levels (ULT) to achieve crystal dissolution, ultimately preventing recurrent gout flares. 10,11 However, previous studies have shown that management of gout is still suboptimal, as many patients either do not receive ULT or do not receive the proper dose of ULT. 12,13 In addition, adherence to ULT is low, 14 resulting in recurrent gout flares. [15][16][17][18] Sodium-glucose cotransporter-2 inhibitors (SGLT2i), which treat type 2 diabetes, 19 reduce the major adverse cardiovascular events and all-cause mortality in individuals with or without diabetes. 20,21 Studies also found that SGLT2i lower serum urate levels and reduce the risk of incident gout. [22][23][24][25][26][27][28][29] However, to date, no study has specifically examined the association of SGLT2i with the risk of recurrent gout flares and all-cause mortality in patients with gout. Using an electronic medical records database from the UK, we conducted a population-based cohort study to compare the risk of recurrent gout flares and all-cause mortality between patients initiating SGLT2i treatment and those initiating 2 other antidiabetic medications (ie, glucagonlike peptide-1 receptor agonists [GLP-1 RA] or dipeptidyl peptidase-4 inhibitors [DPP-4i]) in patients with gout and type 2 diabetes.

Data Source
In this cohort study, we used data from the IQVIA Medical Research Database (IMRD), which incorporated data from The Health Improvement Network, a Cegedim database from general practitioners (GPs) in the UK. The IMRD contains health information on approximately 19 million patients from 839 general practices in the UK. The computerized information includes sociodemographic characteristics, anthropometric characteristics, lifestyle factors, details from visits to GPs, diagnoses from specialist referrals and hospital admissions, as well as results of laboratory tests. The Read classification system is used to code specific diagnoses, whereas a dictionary based on the Multilex classification system is used to code drugs. This study received approval from the medical ethical committee of Xiangya Hospital, with a waiver of informed consent owing to the use of deidentified data, and was approved by the IMRD Scientific Review Committee. The study followed the recommendations of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Study Design and Cohort Definition
We compared the risk of recurrent gout flares between patients initiating SGLT2i treatment and those initiating GLP-1 RA or DPP-4i treatment. 30 We selected DPP-4i and GLP-1 RA as the active comparators because they are novel second-line antidiabetic agents that are similar to SGLT2i and are known to have a neutral effect on serum urate levels in patients with type 2 diabetes. 31,32 We included participants aged 18 to 89 years who had gout and type 2 diabetes from January 1, 2013, to December 31, 2021, and had at least 1 year of continuous enrollment with a general practice prior to entering the study. The diagnosis of gout and type 2 diabetes were based on at least 1 Read code for gout or type 2 diabetes. 33,34 We identified initiators of SGLT2i or active comparators based on whether the first record of the prescription in the IMRD and the prescription date were later than the diagnosis of both gout and type 2 diabetes. The date of the first prescription of either SGLT2i or active comparators was assigned as the index date. We excluded individuals who had a cancer diagnosis or had been prescribed colchicine or the comparators during the year before the index date.

Assessment of Outcomes
The primary outcome was the total number of recurrent gout flares (hereinafter referred to as recurrent flares) during the follow-up period. A gout flare was defined as a recorded Read code of gout plus a recorded prescription of colchicine; a recorded Read code of gout together with at least 1 of intra-articular corticosteroids, nonsteroidal anti-inflammatory drugs, or corticosteroid or adrenocorticotropic hormone within 1 week; or having Read codes specific for gout flare. 35,36 The secondary outcomes consisted of the first recurrent gout flare (hereinafter referred to as the first recurrent flare) and all-cause mortality during the follow-up period.

Assessment of Covariates
Covariates included age, sex, socioeconomic deprivation index score (measured using the Townsend Deprivation Index, which was grouped into quintiles from 1 [least deprived] to 5 [most deprived]), region, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), alcohol use, smoking, gout duration (year from the first gout diagnosis to the index date), type 2 diabetes duration (year from the first type 2 diabetes diagnosis to the index date), Charlson Comorbidity Index, comorbidities at any time since enrolment to the index date, medication use, and use of health care services (number of hospitalizations, visits to general practice, and referral to specialists) during the 1 year before the index date. The details of comorbidities and medication use are listed in Table 1.

Statistical Analysis
Participants were allocated into one of the nine 1-year blocks (ie, 2013-2021) based on the date of initiation of either SGLT2i or active comparator treatment. Within each 1-year time block, we assembled a cohort of SGLT2i initiators and a cohort of initiators of active comparators. In each 1-year time block, we calculated propensity scores for SGLT2i initiation conditional on the aforementioned baseline characteristics. We applied overlap weighting of the propensity scores to balance baseline characteristics between the comparison groups. 30 The overlap weight is defined as 1 minus the propensity score for a treated unit and a propensity score for a comparison unit. Thus, patients with a propensity score of 0.5 make the largest contribution to the effect estimate, and patients with a propensity score close to 0 or 1 make the smallest contribution, therefore smoothly reducing the influence of patients at the tails of the propensity score distribution without making any exclusions and eliminating the potential bias that can arise from the multiplication of scores of the few patients with extremely high or low propensity scores. We assessed the distribution of baseline characteristics between 2 comparison cohorts before and after overlap weighting using the absolute standardized differences. Participants were followed up from the day of initiating medication under the study to the first of the following events to occur: disenrolled from a GP, age of 90 years, death, or the end of the study (ie, March 31, 2022). We calculated the weighted incidence rate for the recurrent flares and estimated the weighted absolute rate difference (RD) between 2 comparison cohorts. We calculated the relative rate (RR) and its 95% CI using a Poisson regression model. Missing values of BMI, smoking status, alcohol consumption, and socioeconomic deprivation index score were imputed using a sequential regression method. To minimize random error, we imputed 5 data sets using Rubin rules. 37 We performed several sensitivity analyses to assess the robustness of the study findings. First, we compared the rate of recurrent flares between patients who initiated SGLT2i treatment and each of the active comparators (ie, DPP-4i and GLP-1 RA). Second, we conducted an as-treated analysis to account for nonadherence to medications under investigation. Specifically, we censored the  To examine whether the risk of the recurrent flares increased during the early period after initiating either SGLT2i or its active comparators, we estimated the monthly risk of the recurrent flares over the first 12 months. For the first recurrent flare analysis, the follow-up ended at the first of the following events: the occurrence of the first recurrent flare, disenrolled from a GP, age of 90 years, death, or the end of the study. We calculated the weighted incidence rate for the first recurrent flare and estimated the RD between 2 comparison cohorts. We performed a Cox proportional hazards model analysis to obtain a hazard ratio (HR) and its 95% CI of the first recurrent flare. We adopted the subdistribution hazard function to account for the competing event of death. 38 Finally, we examined the association of SGLT2i vs active comparators with the risk of all-cause mortality using the Cox proportional hazards model. We also compared the risk of all-cause mortality between

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SGLT2i initiators and each of the active comparators separately.
All P values were 2-sided, and P < .05 was considered statistically significant for all tests. All statistical analyses were performed with SAS software, version 9.4 (SAS Institute Inc).

Results
Among the 5931 patients included in the analysis (mean Before propensity score overlap weighting, compared with those initiating treatment with active comparators, those initiating SGLT2i treatment were younger and more likely to be men; had higher c Measured by a weighted score of 17 comorbidities, which ranged from 0 (none) to 37.
Higher scores indicate higher predicted mortality rate.
BMI and lower levels of serum urate; had a lower prevalence of hypertension, stroke, osteoarthritis, venous thromboembolism, chronic kidney disease, and prescriptions of antihypertensive medicine, other antidiabetic medicine, aspirin, and diuretics; and less use of health care services. After propensity score overlap weighting, the distribution of the characteristics of the 2 comparison cohorts was well balanced (all standardized differences <0.001) ( Table 1) (Table 2). Furthermore, the risk of gout flares increased during the first 3 months after allopurinol initiation and then leveled off (eFigure 4 in Supplement 1).

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a Active comparators consist of DPP-4i and GLP-1 RA.

Discussion
Using the UK population-based database, we found that initiating SGLT2i treatment was associated with a lower risk of recurrent gout flares among the patients with gout and type 2 diabetes. Unlike other ULT medications, we did not observe an apparent transient increase in the risk of gout flares shortly after initiating SGLT2i therapy. In addition, SGLT2i initiators had lower all-cause mortality than DPP-4i initiators.
Previous post hoc analyses of randomized clinical trials [23][24][25]27 showed that SGLT2i reduced serum urate level, incident hyperuricemia, and incident gout in patients with type 2 diabetes or chronic heart failure, compared with placebo. Several observational studies 22,26,28,29 also reported that initiation of SGLT2i treatment was associated with a lower risk of incident gout than initiation of DPP-4i or GLP-1 RA treatment in patients with type 2 diabetes. However, to our knowledge, no study has previously assessed whether SGLT2i reduces the risk of recurrent gout flares. Our study fills this knowledge gap and demonstrates that initiating SGLT2i treatment was associated with a lower rate of recurrent flares than initiating DPP-4i or GLP-1 RA treatment in patients with gout and type 2 diabetes.
Several biological mechanisms may explain our findings. First, SGLT2i could reduce serum urate concentration by increasing kidney urate elimination. 39 This effect is attributed to the glucose in the urine competing with soluble urate for glucose transporter 9-mediated reabsorption in the proximal tubule due to the reduced transport function of SGLT2. 40 Additionally, SGLT2i enhance sirtuin-1, an enzyme that inhibits xanthine oxidase and decreases serum urate levels. 41 Second, SGLT2i may suppress pyrin domain-containing 3 inflammasome activation and attenuate interleukin 1β secretion 42 and thus may lower the risk of gout flares. Finally, studies have shown that SGLT2i could improve kidney function and heart failure and reduce the use of loop or thiazides diuretics, 19,20,43 which may indirectly lower the risk of recurrent gout flares.

Strengths and Limitations
Several strengths of our study are worth noting. First, we implemented an active-comparator new-user design to assess the risk of recurrent flares associated with SGLT2i use. This design helps minimize the confounding by indication and prevalent user biases. Second, no ULT medications have shown a protective effect on all-cause mortality in patients with gout. Although we did not observe a significant reduction of all-cause mortality during the early years of follow-up after initiating SGLT2i treatment, our findings suggest that SGLT2i may be associated with a reduced risk of all-cause mortality. This finding is consistent with previous studies that have shown a similar association, 21 enhancing the credibility of our findings regarding the risk of gout flares. Third, we used the sequential overlap-weighting method to control for confounding; and the age-and sex-adjusted effect estimates are similar to those generated from the overlap-weighted method, indicating that any residual confounding, if present, is unlikely to explain away the association of SGLT2i with either the risk of recurrent gout flares or all-cause mortality.
This study also has some limitations. First, the IMRD does not contain hospitalization data, and some patients may not seek care from GPs for recurrent gout flares. Additionally, the ascertainment of gout flares using a pragmatic approach may lead to a misclassification. As a result, the risk of recurrent gout flare might be underestimated. Nevertheless, it is worth noting that, for gout flares identified by a recorded Read code of gout along with treatments within 1 week, approximately 86% of patients in our study had a documented code for gout on the same date as a prescription of nonsteroidal anti-inflammatory drugs or corticosteroids, and the remaining patients had a recorded code for gout within 7 days before the prescription. Although the therapeutic use of colchicine has extended to other disorders (eg, cardiovascular disease), we would expect patients to take colchicine continuously. When colchicine is prescribed for a discrete episode, it is more often to patients who experienced gout flares. 10,44 In addition, we demonstrated that the risk of gout flares increased during the first 3 months after initiating allopurinol and then leveled off, which is comparable to the findings of the previous randomized clinical trials. 45 All this evidence suggests a reasonable level of ascertainment for gout flares. Furthermore, if gout flares were misclassified, such misclassification is likely nondifferential and biases the results toward the null. Second, we could not evaluate the association of SGLT2i with the risk of recurrent gout flares and mortality among the population who seek care outside the GP system included in IMRD; however, this limitation should not affect the internal validity of the current findings. Third, physician-ordered prescriptions may not reflect the actual medication taken by the patients. However, we found that the results from the intention-totreat analysis did not differ materially from those of the as-treated analysis, suggesting that the potential bias from nonadherence may not be substantial.

Conclusions
In this cohort study of patients with gout and type 2 diabetes, initiating SGLT2i treatment was associated with a reduced risk of recurrent gout flares compared with initiating DPP-4i or GLP-1 RA treatment. Furthermore, SGLT2i initiators had a lower all-cause mortality than initiators of DPP-4i.
These findings suggest that SGLT2i might hold potential in reducing the burden of recurrent gout flares and potentially narrowing the mortality gap between patients with gout and the general population.